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The effect of lymphoid irradiation on progression of joint damage in intractable rheumatoid arthritis.

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LETTERS
146
We have administered thalidomide to 17 patients
with severe RA (manuscript in preparation). Fifteen received 400-600 mg of thalidomide daily, for a mean of 24.8
weeks (range 7-65 weeks). Two patients withdrew before
the sixth week because of side effects: 1 patient because of
drowsiness and the other because of nausea and vomiting.
Twelve patients experienced complete remissions of RA; of
these, only 2 developed symptoms of peripheral sensory
neuropathy . Both women were receiving their second course
of treatment when they experienced a relapse of RA after
initial short-term remissions. Their thalidomide dosage was
600 mgiday (12.8 mgikg and 7.5 mdkg); in weeks 31 and 30,
respectively, they began to experience sensory disturbances, i.e., pins and needles in hands and feet, but there
were no motor problems or alterations in deep tendon
reflexes. Thalidomide therapy was stopped. The neurologic
phenomena improved a few weeks later, and disappeared
completely in 6 months.
Two other patients received 300 mg/day of thalidomide for 62 and 65 weeks. Although there was no improvement in RA, they did not manifest symptoms of neuropathy.
The dissimilarity in findings is noteworthy. Leprologists we consulted agreed with our findings, emphasizing that
neuropathy in patients with erythema nodosum leprosum who
are being treated with thalidomide, even for long periods, is
rare, an observation already noted by Sheskin (2). On the
contrary, in other studies the incidence of thalidomideinduced neuropathy in PN patients has been very high (1,3,4);
this, perhaps, is because PN is associated with a chronic
neuropathy , which would make patients more susceptible to
further damage caused by thalidomide (4). This seems to be
related to the accumulation of pyruvic acid, due to the
inhibitory effect of thalidomide on pyruvate-oxidase (5).
We have been using thalidomide for treatment of
severe cases of RA that is refractory to the conventional
therapies. In women, use of the drug is restricted to those
who are infertile or those who are using adequate contraceptive measures. We believe that, for patients with severe
refractory RA, the use of thalidomide is, perhaps, a useful
option that has frequent side effects but none that are
life-threatening.
Oscar Gutierrez-Rodriguez, MD
PCretz Starusta-Bacal, MD
Hospital Universitario Evaristo Garcia
Oscar Gutierrez-Montes, MD
Hospital Cariuveralejo
Cali, Colombia
1. Sheehan NJ: Thalidomide neurotoxicity and rheumatoid arthritis
(letter). Arthritis Rheum 29: 1296, 1986
2. Sheskin J: Therapeutische Erfahrungen uber den Einfluss des
Thalidomids bei der Lepra-Reaktion. Hautarzt 26: 1-5, 1975
3. Clemmensen OJ, Olsen PZ, Andersen KE: Thalidomide neurotoxicity. Arch Dermatol 120:338-341, 1984
4. Aronson IK, Yu R, West DP, van den Broek H, Antel J:
Thalidomide-induced peripheral neuropathy. Arch Derrnatol
120: 1466-1 470, 1984
5 . Belaube P, Garcin G , Marchand JP, Privat Y: Faut-il rehabiliter
la thalidomide? Sem Hop Paris 59:3101-3104, 1983
The effect of lymphoid irradiation on the progression
of joint damage in intractable rheumatoid arthritis
To the Editor:
The use of lymphoid irradiation (LI) in patients with
intractable rheumatoid arthritis (RA) has been studied at
several centers (1-5). Total doses of 22,000 rads have
induced a sustained reduction in articular disease activity for
up to 40 months (3,4). A randomized, double-blind, comparative study over 12 months showed that treatment with
750-rad LI was as effective as 2,000-rad LI (5).
Little information is available concerning the effects
of LI on progressive joint destruction, as measured radiologically. Because this is an important potential effect of
treatment, we evaluated radiologic progression in 20 RA
patients who were given 750- or 2,000-rad doses of LI. A
detailed account of the clinical and laboratory response to
therapy in these patients has been previously reported (5).
The patients had disease for at least 18 months, and
there was radiologic evidence of joint erosion and persistent
involvement of multiple joints despite conventional drugs,
rest, and physical therapy. They had failed to respond or had
intolerable side effects to 2 or more slow-acting antirheumatic drugs. Plain anteroposterior radiographs of the hands and
feet were taken at the commencement of treatment and after
6 months and 12 months of treatment.
For comparative purposes, a cohort of 22 patients
was evaluated. Eleven of these had received penicillamine
(500 mglday), and the remaining 11 received auranofin (6
mglday). All had active disease at the beginning of treatment
and received continuous therapy for 12 months. The rationale for the selection and analysis of such patients has been
explained elsewhere (6,7). Plain radiographs of the hands
and feet were taken at 0, 6, and 12 months of therapy. These
patients, who were not intended to be a matched control
group, had less severe disease than those patients who
underwent LI.
Radiographs were analyzed by comparison with the
standard films of Larsen et a1 (8). The proximal interphalangeal and metacarpophalangeal joints were scored on a
0-5-point scale. Each wrist joint was similarly scored, but
the score then was multiplied by 5. The interphalangeal joint
of the hallux and the second to fifth metatarsophalangeal
joints were also scored on a 0-5 scale. When the scores were
added, a 0-200 scale was obtained. Radiologic progression
was calculated as (a) absolute changes in the Larsen score,
determined by subtracting the score of the initial film from
that of the 6-month film, or the 6-month film from the
12-month film; and (b) relative change, as a percentage of the
maximum possible change of the Larsen score, calculated by
dividing the change in the score by the maximum possible
increase. This maximum possible increase was obtained by
subtracting the initial score from 200 (9). Radiographs were
read, at a single session, by 3 observers who were “blinded”
to details of the date of the radiograph and the patient’s
therapeutic history. A reconciled grade for each joint was
recorded. (We are indebted to A. Greenwood and R. Bryans
for their assistance in this phase of the study.) Details of the
LETTERS
147
reproducibility and accuracy of our radiologic scoring have
been previously published (10,ll).
Patients given 750- or 2,000-rad doses of LI showed
progressive joint damage, with increases in Larsen scores.
The absolute changes were similar in both groups. Relative
changes were more evident when the rates of progression
were compared (Figure 1). The relative mean increases in
patients given 2,000 rads were similar in the first and second
6-month periods, at 4.9% and 5.0%, respectively. The patients who received 750-rad doses had a greater relative
change in the first 6 months than in the second 6 months
(mean 13.0% versus 8.7%). The relative increase in Larsen
score for the entire 12 months in patients given 750 rads was
just over twice that of those receiving 2,000 rads (21.7%
compared with 9.9%). In patients given 2,000 rads, the
relative changes of increasing joint damage were similar to
those seen in patients given auranofin or penicillamine. The
spread of the data in each group was such that, using
Student’s unpaired t-test, these differences were not significant at the 5% level ( P > 0.05). Alternative statistical
analysis, using Wilcoxon’s rank sum test for unpaired samples and analysis of variance, failed to show significant
differences at the 5% level between the 2 groups.
No previous studies have evaluated the impact of LI
T
a
li 3
b
d
C
Figure 1. Relative changes in Larsen scores (% increase in damage)
over a 12-month-period, in 20 patients who received lymphoid
irradiation (LI) versus 22 patients who were treated with auranofin
(6 mg/day) or penicillamine (500 mglday). a, Increase during the first
6 months of LI. b, Increase during the second 6 months of LI. c,
Overall increase during LI. d, Comparative overall increase in
patients treated with auranofin or penicillamine. Values shown are
the mean and SEM. 0 = 2,000 rads LI; W = 750 rads L1; 0 =
auranofin/penicillamine treatment.
upon radiologic progression in RA. Because of the toxic
complications that occur with therapy, all studies have
assessed a small number of subjects (1-5) and often have not
used untreated controls. Our results suggest that radiologic
progression may be retarded by high-dose (2,000-rad) LI to
the extent seen with second-line or slow-acting antirheumatic drugs such as gold or penicillamine, but not by low-dose
(750-rad) LI.
In view of the small number of patients given LI in
this study, and the possibility that there is a clinically
important effect (a 50% reduction in the rate of radiologic
progression in patients treated with high-dose radiotherapy),
the sample size necessary to reach a satisfactory endpoint
without introducing a Type I1 statistical error was considered. Using the difference in mean values obtained in this
study and maintaining a similar spread of data, 25 patients in
each group would be needed to show a difference which
would be significant at the 5% level using Student’s unpaired
t-test, with the calculations based on relative increases in
Larsen score.
David L. Scott, MD, FRCP
St. Bartholomew’s Hospital
London, U K
John G . Hanly, MD, MRCPI
Michael Moriarty, FRCPI, FRCR
Barry Bresnihan, MD, FRCP
St. Vincent’s Hospital
Dublin. Ireland
I . Kotzin BL, Strober S, Engleman EG, Calin A, Hoppe RT,
Kansas GS, Terrell VP, Kaplan HS: Treatment of intractable
rheumatoid arthritis with total lymphoid irradiation. N Engl J
Med 305:969-976, 1981
2. Trentham DE, Belli JA, Anderson RJ, Buckley JA, Goetzl EJ,
David JR, Austen KF: Clinical immunologic effects of fractionated total lymphoid irradiation in refractory rheumatoid arthritis. N Engl J Med 305:976-982, 1981
3. Field EH, Strober S, Hoppe RT, Calin A, Engleman EG, Kotzin
BL, Tanay AS, Calin HJ, Terrell CP, Kaplan HS: Sustained
improvement of intractable rheumatoid arthritis after total lymphoid irradiation. Arthritis Rheum 26:937-946, 1983
4. Brahn E, Helfgott SM, Belli JA, Anderson RJ, Reinherz EL,
Schlossman SF, Austen KF, Trentham DE: Total lymphoid
irradiation therapy in refractory rheumatoid arthritis: fifteen- to
forty-month followup. Arthritis Rheum 27:481-488, 1984
5. Hanly JG, Hassan J, Moriarty M, Barry C, Molony J, Casey E,
Whelan A, Feighery C, Bresnihan B: Lymphoid irradiation in
intractable rheumatoid arthritis: a double-blind, randomized
study comparing 750-rad treatment with 2,000-rad treatment.
Arthritis Rheum 29:16-25, 1986
6. Scott DL, Grindulis KA, Struthers GR, Coulton BL, Popert AJ,
Bacon PA: The progression of radiological changes in rheumatoid arthritis. Ann Rheum Dis 43:8-17, 1984
7. Scott DL, Dawes PT, Fowler PD, Grindulis KA, Shadforth M,
Bacon PA: Anti-rheumatic drugs and joint damage in rheumatoid arthritis. Q J Med 54:49-59, 1985
8. Larsen A, Dale K, Eek M: Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films.
Acta Radio1 [Diagn] (Stockh) 18:481-491, 1977
9. Scott DL, Dawes PT, Fowler PD, Shadforth MF: Calculating
radiological progression in rheumatoid arthritis. Clin Rheumatol
5:445-449, 1986
148
10. Grindulis KA, Scott DL, Struthers GR: The assessment of
radiological changes in the hands and wrists in rheumatoid
arthritis. Rheumatol l n t 3:39-42, 1983
11. Scott DL, Coulton BL, Bacon PA, Popert AJ: Methods of X-ray
assessment in rheumatoid arthritis: a re-evaluation. Br J Rheumatol 24:21-39, 1985
Impotence in scleroderma
To the Editor:
Scleroderma is a systemic disease associated with
abnormalities in blood vessels that result in fibrosis of
multiple organs (1). No endocrinologic, neurologic, urologic,
or psychological cause has been found. Recently, impotence
has been recognized as a symptom, perhaps even a presenting symptom, of the disease (2-8).
We describe a patient with rapidly progressive scleroderma who developed impotence early in the course of his
disease. The patient, a 66-year-old man, was unable to
perform his usual job because of decreased mobility of his
hands and generalized stiffness. He reported a 14-month
history of progressive thickening of the skin on his hands,
arms, and face, as well as a 12-month history of progressive
inability to have erections, although his libido was intact. He
did not have Raynaud’s phenomenon. The patient and his
wife had had an active, satisfying sexual relationship and he
had fathered 1 1 children.
He denied a change in testicular size, recent trauma
to the testes, or a history of mumps orchitis. Nontender
gynecomastia, not associated with alcohol ingestion or liver
disease, had been present since early adulthood and was
unchanged. He felt otherwise well.
On physical examination, the vital signs were normal. There were small areas of depigmentation on the scalp,
ears, and eyelids. The skin was thickened over the forehead,
eyes, hands, and penis and was hidebound over the forearms, legs, and thighs. Testicular size was normal. Results of
chest roentgenogram and other routine laboratory tests were
normal. There was no evidence of esophageal, renal, or
pulmonary abnormalities. Results of a test for antinuclear
antibodies were positive at a titer of 1:256 with a nucleolar
pattern. Results of a test for anti-double-stranded DNA was
negative. Growth hormone studies, thyroid function tests,
and prolactin level studies were performed, and results were
within normal range. Further endocrine testing revealed
normal levels of estradiol, and testosterone levels of 266
ng/dl and 255 ng/dl (normal 300-1,000 ng/dl). The levels of
follicle-stimulating hormone and luteinizing hormone were
mildly elevated. These findings were consistent with a mild
primary hypogonadism. Testosterone, 300 mg intramuscularly, was given repeatedly; however, there was no improvement in impotence. Due to the marked thickening of the
penis, blood pressure could not be recorded. Doppler studies, however, showed that the larger arterial circulation to
the penis was intact.
In a study by Lally and Jimenez (3), records of 43
men with scleroderma were reviewed retrospectively and
impotence as a presenting symptom was found in 5 (12%).
LETTERS
Each patient had an intact libido and had normal results on
endocrinologic, neurologic, and psychological evaluations
(4). Nowlin et a1 (2) compared 10 male patients with scleroderma, 6 of whom were impotent, with 10 age-matched men
with rheumatoid arthritis who were not impotent. No hormonal or neurologic differences were noted between the 2
groups; however, penile blood pressure was significantly
decreased in 4 impotent scleroderma patients and intermediately decreased in the other 2 impotent scleroderma patients, suggesting that in scleroderma, the cause of irnpotence is small blood vessel disease.
Nowlin et al earlier reported on 2 patients with
hypogonadism and scleroderma (5). One of these patients
had Klinefelter’s syndrome, and the other patient’s libido
was decreased, but he was not impotent and when evaluated, had normal testosterone levels. Our patient developed
impotence as his scleroderma progressed. Hypogonadism
was present, but hormone replacement therapy did not alter
the impotence. An association between hypogonadism and
scleroderma has been described, but its significance is unclear and may be related to fibrosis of the testes. Hypogonadism, therefore, is probably not the cause of impotence
in this group of patients. Abnormalities of blood vessels
within the penis, as within the esophagus, skin, and kidney,
occur in scleroderma and are probably the cause of impotence in this disease, posing an additional burden for the
male patient with scleroderma.
Marie Mannino, MD
Catherine Marino, MD
Queens Hospital Center
Jamaica, N Y
1. LeRoy EC: Scleroderma, Textbook of Rheumatology. Second
edition. Edited by W N Kelley, ED Harris Jr, S Ruddy, CB
Sledge. Philadelphia, WB Saunders, 1985, pp 1183-1205
2. Nowlin NS, Brick JE, Weaver DJ, Wilson DA, Judd HL, Lu
JKH, Carlson HE: Impotence in scleroderma. Ann Intern Med
104:7Y4-798, 1986
3. Lally E, Jimenez S: Impotence in progressive systemic sclerosis.
Ann Intern Med 95:150-153, 1981
4. Jimenez S: Impotence in progressive systemic sclerosis (letter).
Ann Intern Med 96:125-126, 1982
5. Nowlin NS, Zwillich SH, Brick JE, Carlson HE: Male hypogonadism and scleroderma. J Rheurnatol 12:605-606, 1985
6. Davidson R: Impotence in progressive systemic sclerosis (letter).
Ann Intern Med 96:125, 1982
7. Klein LE: Progressive systemic sclerosis and impotence (letter).
Ann Intern Med 95:658-659, 1981
8. Stanik Davis S, Viosca S, Guralnik M, Windsor C, Buttiglieri M,
Baker J, Mehta A, Korenman S: Evaluation of impotence in
older men. West J Med 142:499-505, 1985
Diflunisal-associatedthrombocytopenia in a patient
with rheumatoid arthritis
To the Editor:
Thrombocytopenia associated with nonsteroidal
antiinflammatory drug (NSAID) therapy recently has been
reviewed extensively (I). Although it is a relatively rare side
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